Recently we have defined a unique role for metal ions as regulators of the enzymes of heme biosynthesis and degradation and have described a distinct heme b oxygenase enzyme whose production is increased by metal ions such as tin and iron. We have observed that treatment of animals with tin causes a depression in the heart and kidney mitrochondrial content of cytochromes possessing hemes a, B, and c. We have also observed decreases in the heart content of mitochondrial cytochromes in a disease which causes increased heme degradation and the release of iron. Although these decreases were not related to the elevated heme oxygenase activity, it can be postulated that the activity of the enzymes of mitochondrial heme metabolism are also regulated by metal ions. In contrast to the mitochondrial hemoproteins, myoglobin appears to be a substrate for heme oxygenase, and it can be hypothesized that factors which alter the activity of heme oxygenase would directly alter myoglobin turnover. Various metal ions including tin and iron accumulate in the body, and there is substantial evidence relating metal ion toxicity to their effects on the metabolic functions of the heart and kidney. For example, excessive mortality due to heart failure observed in individuals who are occupationally exposed to metal ions is linked to these agents. The proposed studies will encompass the regulatory action of metal ions on the metabolism of mitochondrial hemoproteins and myoglobin. The heart and kidney will be the organs of prime concern, since they have very high requirements for hemoprotein dependent oxidative metabolism. Specifically, these studies will include: 1) the investigation of the effects of tin and iron on the synthesis and the degradation of mitochondrial cytochromes in the heart and kidney, 2) the elucidation of the mechanism of heme c degradation, and 3) the investigation of the effects of increased heme oxygenase activity on the turnover of cardiac myoglobin and the mechanism of myoglobin degradation.